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insulin receptor substrate 1; IRS-1 (IRS1)

Function: - may mediate the control of various cellular processes by insulin - when phosphorylated by the insulin receptor, binds specifically to various cellular proteins containing SH2 domains such as: a) phosphatidylinositol 3-kinase p85 subunit b) GRB2 - activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (putative) - insulin & IL-4 stimulate IRS-1 phosphorylation - insulin induces association of IRS-1 with the integrin alpha-5/beta-3 receptor [5] - Ser phosphorylation of IRS1 is a mechanism for insulin resistance - Ser-312 phosphorylation inhibits insulin action via disruption of IRS1 interaction with the insulin receptor - phosphorylation of Tyr-896 is required for GRB2-binding - interacts with the NPXY motif of Tyr-phosphorylated IGF1R & INSR via the PTB domain - binds to phosphatidylinositol 3-kinase p85 subunit via phosphorylated YXXM motifs - binds ROCK1 - binds to UBTF & PIK3CA in nuclear extracts - interacts with SOCS7 Structure: - contains 1 IRS-type PTB domain - contains 1 PH domain Polymorphism: - the Arg-971 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, & glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway; Arg-971 may contribute to the in vivo insulin resistance observed in carriers of this variant; Arg-971 could contribute to the risk for atherosclerosis associated with non-insulin-dependent diabetes mellitus (NIDDM) by producing a cluster of insulin resistance-related metabolic abnormalities; in insulin-stimulated human endothelial cells from carriers of Arg-971, genetic impairment of the IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired insulin-stimulated nitric oxide (NO) release & suggested that this may be a mechanism through which the Arg-971 polymorphism contributes to the genetic predisposition to develop endothelial dysfunction & cardiovascular disease; Arg-971 not only reduces phosphorylation of the substrate but allows IRS1 to act as an inhibitor of PI3K, producing global insulin resistance Pathology: - polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM)

Interactions

molecular events

General

phosphoprotein

Properties

SIZE: entity length = 1242 aa MW = 132 kD MOTIF: Ser phosphorylation site {S3} PH domain {12-115} MOTIF: Tyr phosphorylation site {Y46} Ser phosphorylation site {S99} glycine-rich region {128-134} phosphotyrosine interaction domain NAME: phosphotyrosine interaction domain SITE: 160-264 serine-rich region {268-444} MOTIF: serine residue (SEVERAL) Ser phosphorylation site {S312} Ser phosphorylation site {S329} Ser phosphorylation site {S345} peptide motif {465-468} MOTIF: Tyr phosphorylation site {Y465} Ser phosphorylation site {S531} peptide motif {551-554} peptide motif {612-615} MOTIF: Tyr phosphorylation site {Y612} Ser phosphorylation site {S629} peptide motif {632-635} MOTIF: Tyr phosphorylation site {Y632} Ser phosphorylation site {S636} peptide motif {662-665} MOTIF: Tyr phosphorylation site {Y662} serine-rich region {680-686} MOTIF: serine residue (SEVERAL) peptide motif {732-735} Ser phosphorylation site {S794} serine-rich region {807-815} MOTIF: serine residue (SEVERAL) glutamine-rich region {877-882} MOTIF: glutamine residue (SEVERAL) binding site SITE: 896-898 FOR-BINDING-OF: growth factor receptor-bound protein-2 (grb2) MOTIF: Tyr phosphorylation site {Y896} peptide motif {941-944} MOTIF: Tyr phosphorylation site {Y941} peptide motif {989-992} MOTIF: Tyr phosphorylation site {Y989} peptide motif {1012-1015} Ser phosphorylation site {S1101} Ser phosphorylation site {S1145} Tyr phosphorylation site {Y1179} proline-rich region SITE: 1192-1210 MOTIF: proline residue (SEVERAL) Ser phosphorylation site {S1223} Tyr phosphorylation site {Y1229}

Database Correlations

OMIM correlations UniProt P35568 PFAM correlations Entrez Gene 3667 Kegg hsa:3667

References

  1. Baltensperger K, Kozma LM, Cherniack AD, Klarlund JK, Chawla A, Banerjee U, Czech MP. Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes. Science. 1993 Jun 25;260(5116):1950-2. PMID: 8391166
  2. Saltiel AR. The paradoxical regulation of protein phosphorylation in insulin action. FASEB J. 1994 Oct;8(13):1034-40. Review. PMID: 7926368
  3. White MF The IRS-1 signaling system. Curr Opin Genet Dev 4:47 1994 PMID: 8193539
  4. Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573-80. Review. PMID: 7531822
  5. Clark EA & Brugge JS Integrins and signal transduction pathways: the road taken. Science 268:233 1995 PMID: 7716514
  6. UniProt :accession P35568

Component-of

molecular complex